|Authors: Edén A, Franklin D, Fuchs D, Grant I, Letendre S, Marcotte T, Nilsson S, Price RW, Zetterberg H, Gisslén M, for the CHARTER group|
Even in patients responding well to current antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) remain prevalent. However, it is unclear if neuronal damage continues despite effective suppression of HIV-1. The light subunit of the neurofilament protein (NFL) is a component of myelinated axons, and elevated concentrations in cerebrospinal fluid (CSF) are a sensitive marker of ongoing axonal injury in HIV-associated dementia (HAD). To investigate if milder forms of neurocognitive impairment – asymptomatic neurocognitive impairment (ANI) and minor neurocognitive disorder (MND) – are associated with ongoing neuronal damage, we analyzed CSF NFL in a well characterized cohort of virally-suppressed subjects on ART with or without ANI/MND.
In a cross-sectional analysis, subjects on ART with plasma HIV-1 RNA <50 c/ml without significant confounding conditions (e.g., current substance dependence) were identified from longitudinal studies (CHARTER and HNRC). Standardized neurocognitive performance (NP) testing was performed. Subjects were classified as NP-normal (NPN) or NP-impaired (ANI/MND) based upon demographically-adjusted norms. Subjects were selected to yield approximately equal samples of NPN, ANI, and MND. CSF concentrations of NFL were measured by an enzymatic 2-site quantitative immunoassay (UmanDiagnostics, Umea, Sweden). CSF neopterin was measured by ELISA. Continuous variables were log10 transformed where appropriate. For two group comparisons, Mann- Whitney-U-test was used. The relationship between CSF NFL levels and age in the two groups were analyzed with a linear mixed effects model. Correlations were calculated using Pearson correlation coefficients test.
100 (91% male) subjects were included in the analysis, 29 NPN and 71 with ANI/MND (ANI=38; MND=33). Median (IQR) age was 47 (41-54) years, with current CD4+ 524 (359-771) and nadir 72 (10-224) x106 cells/l. 97% of participants also had CSF HIV-1 RNA <50 c/ml (remaining 3 subjects < 125 c/ml). No statistically significant difference was found in NFL between the NPN and ANI/MND groups. We found no correlation between CD4 cell count or CD4 nadir and NFL, however CSF neopterin was significantly correlated to NFL in the whole study population (r=0.21; p=0.035) and CSF neopterin was higher in the ANI/MND group (median 7.3, IQR 4.9-12 nmol/l) than in the NPN group (median 4.8, IQR 4.7-7-4 nmol/l) (p<0,01).
In this cross sectional analysis we found no difference in NFL in subjects with ANI/MND compared to subjects without neurocognitive impairment. Interestingly, CSF neopterin was higher in the ANI/MND group indicating an association between increased intrathecal immunoactivation and neurocognitive impairment in patients on ART.|